Numerous methods and vectors for gene therapy have been developed in recent years. A survey is given by Mulligan in Science, 1993, pp. 260, 926. Many vectors are favored for gene therapy, particularly those, which are derived from retroviruses or adenoviruses. Both types of virus vectors are relatively broadly useful. Retroviral vectors are generally effective only in proliferating cells. Adenoviruses also infect nondividing cells. Although both types of vectors are suitable for gene transfer in vitro into liver cells (hepatocytes), but they can hardly be considered for use in in vivo gene therapy in humans. Although a partial liver resection is necessary to stimulate cell division (regeneration) in the application of retroviral vectors, the adenoviral gene transfer is not very stable, because no gene integration into the genome takes place.
Alternative vectors with potential applicability for gene transfer to liver cells are based on liposomes, or are also based on multicomponent particles with protein domains, which bind specifically to receptors of the live cell, such as the asialoglycoprotein receptor, and can be taken up in the cell due to receptor internalization. These were surveyed by Versland et al. in 1992 Seminars in Liver Disease 12, 332. An important disadvantage of these vectors is the endocytotic pathway, which leads to a degration of a large portion of the vectors and their DNA in the endosomes, so that only small amounts of functional DNA can reach the cell nucleus.
A solution to this problem was found for in vitro application, but that is not useful for in vivo use in patients. The principle is based on the simultaneous infection of the target cells with adenovirus, which leads to a disruption of the endosomes and a release of vector (DNA) as described by Curiel, D. T., Agrawal, S., Wagner, E. and Cotten, M. 1991, PNAS 88, 8850-8854.